化学
癌症研究
高通量筛选
细胞毒性
药理学
喹唑啉
细胞凋亡
虚拟筛选
药物发现
淋巴瘤
生物化学
体外
免疫学
生物
组合化学
作者
Xuewu Liang,Chenxia Sun,Chunpu Li,Haolan Yu,Xiaohui Wei,Xuyi Liu,Wei Bao,Yuqiang Shi,Xiaochen Sun,Mirzadavlat Khamrakulov,Chenghua Yang,Hong Liu
标识
DOI:10.1021/acs.jmedchem.1c00466
摘要
Development of mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) inhibitors is of great value and significance in the treatment of neoplastic disorders and inflammatory and autoimmune diseases. However, there is a lack of effective MALT1 inhibitors in clinic. Herein, a novel class of potent 5-oxo-1-thioxo-4,5-dihydro-1H-thiazolo[3,4-a]quinazoline-based MALT1 inhibitors and their covalent derivatives were first identified and designed through high-throughput screening. We demonstrated that compounds 15c, 15e, and 20c effectively inhibited the MALT1 protease and displayed selective cytotoxicity to activated B cell-like diffuse large B cell lymphoma with low single-digit micromolar potency. Furthermore, compound 20c specifically repressed NF-κB signaling and induced cell apoptosis in MALT1-dependent TMD8 cells in a dose-dependent manner. More importantly, 20c showed good pharmacokinetic properties and antitumor efficacy with no significant toxicity in the TMD8 xenograft tumor model. Collectively, this study provides valuable lead compounds of MALT1 inhibitors for further structural optimization and antitumor mechanism study.
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